This application proposes continuation of a program of investigation of hemoglobin and red blood cells in normal human adults and infants, in hemoglobinopathies and in a variety of diseases in which oxygen transport and respiratory function are impaired. The program brings together ten research groups in a common approach directed toward an integrated, multifaceted, multidisciplined study of the hemoglobin-red cell system in health and disease. Sickle cell disease will receive special attention and effort but a variety of hemoglobinopathies will also be included in these studies, as will other human disorders in which oxygen transport and, thus, respiratory function is impaired. Attention will be directed towards: the electronic states of heme iron and the environment of the heme group, conformational and associative behavior of hemoglobin tetramer and its subunits, ligand binding, properties of hemoglobin and linked functions, interactions between hemoglobin and red cell membrane, properties of erythrocyte membrane and flow dynamics of red cells. Details of the chain of structure-function relationships extending from heme group through subunits of hemoglobin to the red cell membrane and the red cell as a whole will be thoroughly explored. A wide spectrum of methodological, technical and investigative approaches will be used in this conjoint study. The ultimate objective will be a complete and unambiguous description of how alterations in primary structure of hemoglobin such as occur in hemoglobin S result in alterations in function that underly the disease state itself.